Genetic Risk Underlying Pediatric Critical Illness

儿科危重疾病的遗传风险

• 批准号: 10739999
• 负责人: Joshua Ethan Motelow
• 金额: $ 25.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739999
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Adverse drug event; Asthma; Biological; Caring; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Management; Clinical Trials; Clinical stratification; Critical Care; Critical Illness; Critically ill children; Data; Databases; Disease; Doctor of Philosophy; Dose; Early Intervention; Enrollment; Environment; Equity; Fellowship; Future; Genes; Genetic; Genetic Risk; Genetics and Medicine; Genome; Genomics; Goals; Hereditary Disease; Heterogeneity; Human Genetics; Hypersensitivity; Immunity; Intervention; Kidney; Lead; Light; Lower Respiratory Tract Infection; Mediating; Medical center; Medicine; Mendelian disorder; Mentors; Mentorship; Methods; Morbidity - disease rate; Network-based; Neurosciences; Oranges; Pathway interactions; Patients; Pediatric Intensive Care Units; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physicians; Positioning Attribute; Postdoctoral Fellow; Predisposition; Proteins; Publishing; Research; Resources; Respiratory Failure; Risk; Risk Factors; Sample Size; Sampling; Scientist; Secondary to; Source; Testing; Time; Training; Universities; Variant; Viral; Virus Diseases; career development; clinical risk; clinically actionable; cohort; comparative efficacy; comparison control; disorder risk; ethical, legal, and social implication; exome; exome sequencing; experimental study; gene network; genetic association; genome sequencing; improved; innovation; loss of function; medication administration; next generation sequencing; novel; novel therapeutics; polygenic risk score; precision medicine; programs; response; risk variant; targeted treatment; therapeutic development; venous thromboembolism

Project Summary/Abstract Children rarely become critically ill. I hypothesize that genetic risk contributes to unexpected pediatric critical illness. Identifying risk groups allows for clinical stratification and targeted therapies, but these benefits can only be realized if risk is known. This proposal will uncover the monogenic (i.e., single gene), polygenic (i.e., many genes), and pharmacogenomic (i.e., genetic effect on drug response) risks contributing to pediatric critical illness. In Aim 1, I apply innovative gene-network discovery methods to uncover monogenic risk for viral respiratory failure, the most common cause of pediatric intensive care unit admission. In Aim 2, I will assess the contribution of polygenic risk to common pediatric intensive care unit morbidities (viral respiratory failure, venous thromboembolism, acute kidney injury). In Aim 3, I will assess pharmacogenomic risk detected by exome and genome sequencing. This K08 will uncover genetic risk in critically ill children which will inform future multi-center genetic association studies and clinical trials to improve care in the pediatric intensive care unit. Candidate: Scientifically, I have a PhD in neuroscience and completed a post-doctoral fellowship in human genetics. Clinically, I am an attending physician in pediatric critical care medicine. There is a need for physician-scientists who can identify unusual disease presentations and uncover novel genetic risk. There is limited application of precision medicine in the pediatric intensive care unit, and I am well positioned to identify opportunities and investigate applications. My goal is to develop an independent research program focused on “the genomics of pediatric critical illness”. During the K08 training period, I will: (1) Refine expertise in gene network discovery, (2) Develop expertise in the novel application of polygenic risk scores to children with critical illness, (3) Develop expertise in pharmacogenomic analysis of exomes and genomes, (4) Become proficient in the Ethical, Legal, and Social Implications (ELSI) of genomics, and (5) Transition to independence. Environment: To guide and support my research and training goals, I have assembled a strong mentorship team of experts in genetics and medicine (Dr Gharavi, Mentor and Dr. Chung, Advisor), polygenic risk scores (Dr. Kiryluk, Advisor), pharmacogenomics (Dr. Jobanputra, Advisor and Dr. Chung, Advisor), statistical genetics (Dr. Ionita-Laza, Advisor), allergy and inborn errors of immunity (Dr. Orange, Advisor), renal genetics (Dr. Gharavi, Mentor and Dr. Kiryluk, Advisor), and Equity and ELSI research (Dr. Sabatello, Advisor). The research will be conducted at Columbia University Irving Medical Center, which will give me access to extensive resources and training to help me successfully transition to independence.

项目概要/摘要 儿童很少会患上危重病，我认为遗传风险会导致意外的儿科危重病。 识别风险群体可以进行临床分层和针对性治疗，但这些好处可以 只有在已知风险的情况下才能实现该建议将揭示单基因（即单基因）、多基因（即， 许多基因）和药物基因组学（即药物反应的遗传效应）风险有助于儿科 在目标 1 中，我应用创新的基因网络发现方法来揭示病毒的单基因风险。 呼吸衰竭是儿科重症监护室入院的最常见原因，我将在目标 2 中进行评估。 多基因风险对儿科​​重症监护病房常见发病率（病毒性呼吸衰竭、 在目标 3 中，我将评估通过检测发现的药物基因组风险。 外显子组和基因组测序将揭示危重儿童的遗传风险，从而提供信息。 未来的多中心遗传关联研究和临床试验，以改善儿科重症监护的护理 候选人：从科学角度来说，我拥有神经科学博士学位，并完成了博士后奖学金。 临床上，我是儿科重症监护医学的主治医师。 能够识别异常疾病表现并发现新的遗传风险的医生科学家。 精准医学在儿科重症监护病房的应用有限，我有能力识别 我的目标是开发一个独立的研究项目，重点关注。 “儿科危重疾病基因组学”。在K08培训期间，我将：（1）完善基因专业知识。 网络发现，(2) 发展多基因风险评分在儿童中的新应用的专业知识 危重疾病，(3) 发展外显子组和基因组药物基因组学分析方面的专业知识，(4) 成为 精通基因组学的伦理、法律和社会影响 (ELSI)，以及 (5) 向独立过渡。 环境：为了指导和支持我的研究和培训目标，我组建了强大的导师团队 遗传学和医学专家团队（导师 Gharavi 博士和顾问 Chung 博士），多基因风险评分 （Kiryluk 博士，顾问），药物基因组学（Jobanputra 博士，顾问和 Chung 博士，顾问），统计 遗传学（Ionita-Laza 博士，顾问）、过敏和先天性免疫缺陷（Orange 博士，顾问）、肾脏遗传学 （Gharavi 博士，导师和 Kiryluk 博士，顾问），以及股权和 ELSI 研究（Sabatello 博士，顾问）。 研究将在哥伦比亚大学欧文医学中心进行，这将使我能够获得 广泛的资源和培训帮助我成功过渡到独立。